ECE2024 Poster Presentations Endocrine-Related Cancer (40 abstracts)
Growth differentiation factor 15 (GDF-15) is induced by mitotane in adrenocortical carcinoma and associated with poor prognosis and impaired responsiveness to immunotherapy
Isabel Weigand 1 , Alexandra Triebig 1 , Maier Tanja 1 , Tanja Anderlik 2 , Hanna Remde 2 , Laura-Sophie Landwehr 2 , Otilia Kimpel 2 , Miriam Reuter 2 , Jochen Schreiner 1 , Florian Wedekink 3 , Eva Hoster 4 , Paul Schwarzlmueller 1 , Martin Reincke 1 , Jörg Wischhusen 3 , Martin Fassnacht 5 & Kroiss Matthias 1
1LMU University Hospital, Department of Internal Medicine IV, Germany; 2University Hospital Würzburg, Department of Internal Medicine I, Germany; 3University Hospital Würzburg, Department of Obstetrics and Gynecology, Germany; 4Ludwig-Maximilians-University, Institute for Medical Informatics, Biometry and Epidemiology, Germany; 5University Hospital Würzburg, Department of Internal Medicine I, Germany
Background: Treatment of adrenocortical carcinoma (ACC) is unsatisfactory in advanced stages. Oral mitotane remains a mainstay of treatment. Response rates of ACC to immune checkpoint inhibition (ICI) are disappointing and markers of response have not been identified. Tumoural infiltration with cells of the adaptive immune system is sparse in ACC tissue. Growth/differentiation factor 15 (GDF-15) is a cytokine that has been described to impair tumoral immune infiltration and is explored as a treatment target. We previously found GDF-15 to be induced in ACC cells upon mitotane treatment.
Aim: To assess the value of serum GDF-15 for the diagnosis of ACC, as a predictor of prognosis and serum marker of response to ICI.
Methods: Clinical data from patient records were retrieved. GDF-15 was measured in serum samples. 151 patients had ACC (99 prior, 52 during mitotane) and 42 patients benign adrenal tumors (ACA). Serum GDF-15 was analyzed in a second cohort of 27 ACC patients, including 11 responders, who received ICI. mRNA expression of GDF-15 and genes related to immune response was quantified in 58 ACC tumour samples.
Results: Serum GDF-15 did not differ significantly between patients with ACC and ACA. In 40 paired specimens from patients with active ACC, serum GDF-15 increased from 0.6±2.2 ng/ml prior mitotane to 2.3±3.9 ng/ml after mitotane initiation (P<0.0001). Plasma mitotane significantly correlated with serum GDF-15 (Spearman r=0.58). In ACC patients, serum GDF-15 below the median of 0.81 before and 2.17 ng/ml after mitotane was associated with significantly longer patient survival compared to GDF-15 above the median. After adjustment for ENSAT stage and Ki-67 index, this association remained statistically significant with hazard ratios of 2.3 (95% CI 1.14–4.81, P=0.021) and 2.9 (95% CI 1.28–6.82, P=0.01), respectively. GDF-15 levels in responders to ICI were significantly lower than in non-responders (P=0.039) and patients with serum GDF-15 below the median (4.4 ng/ml) showed a trend towards longer progression-free survival with ICI. Expression of pro-inflammatory immune-related genes was lower in ACC tissue with GDF-15 expression above the median.
Conclusion: Mitotane induces GDF-15 secretion and is associated with poor overall survival and impaired response to ICI. Hence, GDF-15 may serve as a serum marker of disease and response to ICI in ACC. GDF-15 may contribute to sparse tumoural infiltration with immune cells in ACC.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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